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(Circulation. 1998;97:645-650.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Induction of Neoangiogenesis in Ischemic Myocardium by Human Growth Factors

First Clinical Results of a New Treatment of Coronary Heart Disease

B. Schumacher, MD; P. Pecher, MD; B. U. von Specht, MD; ; Th. Stegmann, MD

From the Klinik für Thorax-, Herz und Gefäßchirurgie, Klinikum Fulda, Germany, and Chirurgische Forschung (B.U.v.S.), Universitätsklinik Freiburg, Germany.

Correspondence to B. Schumacher, MD, Klinik für Thorax-, Herz und Gefäßchirurgie, Klinikum Fulda, Pacelliallee 4, D-36043 Fulda, Germany.

Background—The present article is a report of our animal experiments and also of the first clinical results of a new treatment for coronary heart disease using the human growth factor FGF-I (basic fibroblast growth factor) to induce neoangiogenesis in the ischemic myocardium.

Methods and Results—FGF-I was obtained from strains of Escherichia coli by genetic engineering, then isolated and highly purified. Several series of animal experiments demonstrated the apathogenic action and neoangiogenic potency of this factor. After successful conclusion of the animal experiments, it was used clinically for the first time. FGF-I (0.01 mg/kg body weight) was injected close to the vessels after the completion of internal mammary artery (IMA)/left anterior descending coronary artery (LAD) anastomosis in 20 patients with three-vessel coronary disease. All the patients had additional peripheral stenoses of the LAD or one of its diagonal branches. Twelve weeks later, the IMA bypasses were selectively imaged by intra-arterial digital subtraction angiography and quantitatively evaluated. In all the animal experiments, the development of new vessels in the ischemic myocardium could be demonstrated angiographically. The formation of capillaries could also be demonstrated in humans and was found in all cases around the site of injection. A capillary network sprouting from the proximal part of the coronary artery could be shown to have bypassed the stenoses and rejoined the distal parts of the vessel.

Conclusions—We believe that the use of FGF-I for myocardial revascularization is in principle a new concept and that it may be particularly suitable for patients with additional peripheral stenoses that cannot be revascularized surgically.

Key Words: growth substances • angiogenesis • coronary disease

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				M. A. S. Rajanayagam, M. Shou, V. Thirumurti, D. F. Lazarous, A. A. Quyyumi, L. Goncalves, J. Stiber, S. E. Epstein, and E. F. Unger Intracoronary basic fibroblast growth factor enhances myocardial collateral perfusion in dogs J. Am. Coll. Cardiol., February 1, 2000; 35(2): 519 - 526. [Abstract] [Full Text] [PDF]

				R. Kornowski, S. Fuchs, M. B. Leon, and S. E. Epstein Delivery Strategies to Achieve Therapeutic Myocardial Angiogenesis Circulation, February 1, 2000; 101(4): 454 - 458. [Abstract] [Full Text] [PDF]

				R. C. Hendel, T. D. Henry, K. Rocha-Singh, J. M. Isner, D. J. Kereiakes, F. J. Giordano, M. Simons, and R. O. Bonow Effect of Intracoronary Recombinant Human Vascular Endothelial Growth Factor on Myocardial Perfusion : Evidence for a Dose-Dependent Effect Circulation, January 18, 2000; 101(2): 118 - 121. [Abstract] [Full Text] [PDF]

				M. Fleisch, M. Billinger, F. R. Eberli, A. R. Garachemani, B. Meier, and C. Seiler Physiologically Assessed Coronary Collateral Flow and Intracoronary Growth Factor Concentrations in Patients With 1- to 3-Vessel Coronary Artery Disease Circulation, November 9, 1999; 100(19): 1945 - 1950. [Abstract] [Full Text] [PDF]

				R. J. Laham, F. W. Sellke, E. R. Edelman, J. D. Pearlman, J. A. Ware, D. L. Brown, J. P. Gold, and M. Simons Local Perivascular Delivery of Basic Fibroblast Growth Factor in Patients Undergoing Coronary Bypass Surgery : Results of a Phase I Randomized, Double-Blind, Placebo-Controlled Trial Circulation, November 2, 1999; 100(18): 1865 - 1871. [Abstract] [Full Text] [PDF]

				G.C. Hughes, B. H. Annex, B. Yin, A. M. Pippen, P. Lin, A. P. Kypson, K. G. Peters, J. E. Lowe, and K. P. Landolfo Transmyocardial laser revascularization limits in vivo adenoviral-mediated gene transfer in porcine myocardium Cardiovasc Res, October 1, 1999; 44(1): 81 - 90. [Abstract] [Full Text] [PDF]

				C. Seiler Human Basic Fibroblast Growth Factor Induces Angiogenesis in Hen Eggs and Rat Hearts Circulation, September 14, 1999; 100 (11): 1250 - 1252. [Full Text] [PDF]

				J. F. Symes, D. W. Losordo, P. R. Vale, K. G. Lathi, D. D. Esakof, M. Mayskiy, and J. M. Isner Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease Ann. Thorac. Surg., September 1, 1999; 68(3): 830 - 836. [Abstract] [Full Text] [PDF]

				J. R Kersten, P. S Pagel, W. M Chilian, and D. C Warltier Multifactorial basis for coronary collateralization: a complex adaptive response to ischemia Cardiovasc Res, July 1, 1999; 43(1): 44 - 57. [Abstract] [Full Text] [PDF]

				T. D Henry Science, medicine, and the future: Therapeutic angiogenesis BMJ, June 5, 1999; 318(7197): 1536 - 1539. [Full Text]

				T. Hasegawa, A. Kimura, M. Miyataka, M. Inagaki, and K. Ishikawa Basic Fibroblast Growth Factor Increases Regional Myocardial Blood Flow and Salvages Myocardium in the Infarct Border Zone in a Rabbit Model of Acute Myocardial Infarction Angiology, June 1, 1999; 50(6): 487 - 495. [Abstract] [PDF]

				A. Sahni, L. A. Sporn, and C. W. Francis Potentiation of Endothelial Cell Proliferation by Fibrin(ogen)-bound Fibroblast Growth Factor-2 J. Biol. Chem., May 21, 1999; 274(21): 14936 - 14941. [Abstract] [Full Text] [PDF]

				L. M. Mir, M. F. Bureau, J. Gehl, R. Rangara, D. Rouy, J.-M. Caillaud, P. Delaere, D. Branellec, B. Schwartz, and D. Scherman High-efficiency gene transfer into skeletal muscle mediated by electric pulses PNAS, April 13, 1999; 96(8): 4262 - 4267. [Abstract] [Full Text] [PDF]

				J. M. Isner Cancer and Atherosclerosis : The Broad Mandate of Angiogenesis Circulation, April 6, 1999; 99(13): 1653 - 1655. [Full Text] [PDF]

				A. Basile-Borgia, J. H Abel, and H. Mahloogi Molecular advances in cardiac and cardiovascular disease Perfusion, March 1, 1999; 14(2): 89 - 99. [Abstract] [PDF]